DESCRIPTION: (Applicant's Abstract) We plan to utilize a unique proprietary transgenic mouse line engineered to produce human immunoglobulins in order to generate human monoclonal anti-cocaine antibodies. These human antibodies should prove suitable for passive immunotherapy of cocaine dependent patients resulting in an effective treatment for cocaine addiction. The use of human monoclonal anti-cocaine antibodies should negate the problem of species incompatibility which has to date restricted the use of passive immunotherapy. Investigators actively working on the development and assessment of cocaine pharmacotherapy as part of our NIDA sponsored Medication Development Research Unit are collaborating with a group of academic and industrial investigators actively developing novel immunotherapy techniques. The overall goals of this SPIRCAP proposal are: 1) Generate in the transgenic mice an anti-cocaine human IgG immune response. Then produce, identify and isolate spleen cell-mouse myeloma hybridomas secreting individual human anti-cocaine monoclonal antibodies. 2) Characterize the purified antibodies with respect to their affinity and specificity for cocaine binding relative to cocaine metabolites and related compounds. 3) Determine the effects of selected human anti-cocaine antibodies on the behavioral effects and on the pharmacokinetics of cocaine in rats and select the best candidate for advancement. 4) Scale-up production of the anti-cocaine monoclonal antibody to FDA-required purity standards in sufficient quantities for animal toxicity studies and then phase 1 human safety trials. 5) Assess animal toxicity of a characterized anti-cocaine antibody in a GLP facility and file and IND application with the FDA to proceed into phase 1 clinical trials. 6) Determine any toxicity and measure the pharmacokinetics of the antibody in humans. The success of this SPIRCAP program will be defined by the ability of a human anti- cocaine antibody to safely modify the pharmacokinetics of cocaine and significantly decrease CSF concentrations of cocaine. These studies will form the basis for an application to the FDA for advancement of an identified human monoclonal anti-cocaine antibody to Phase II clinical trials to determine the efficacy of a passive immunotherapy of cocaine abuse.